In drug development, physiological effects of a test substance have conventionally been assessed using anesthetized, restrained animals. Tests under such conditions, however, are under severe impact of stress and anesthesia, and hard to allow precise evaluation of the effects of a test substance.
Recent safety pharmacology studies for drug development are conducted mostly on unanesthetized, unrestrained test animals under the conditions as stress-free as possible, so as to precisely evaluate the effects of a test substance. The objectives of the safety pharmacology studies are to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety; to evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies; and to investigate the mechanism of adverse pharmacodynamic effects observed and/or suspected. Currently, tests on the respiratory, central nervous, and cardiovascular systems are mandatory.
In the respiratory test, parameters such as respiratory rate and respiratory function after administration of a test substance are evaluated for properly assessing the effects of the test substance on the respiratory system. In the central nervous test, motor activity, behavioral changes, coordination, sensory/motor reflex responses, body temperature, and the like after administration of a test substance, are monitored for assessing the effects of the test substance on the respiratory system. In the cardiovascular test, blood pressure, heart rate, electrocardiogram, and the like after administration of a test substance, are evaluated for assessing the effects of the test substance on the cardiovascular system.
Before conducting the respiratory, central nervous, and cardiovascular tests, test animals are often acclimatized to the environment for mitigating stress and other purposes.
However, animals having a higher level of intelligence, such as monkeys, dogs, and pigs, sometimes experience difficulties in acclimatization, depending on the test contents. In particular, the respiratory test has to be conducted with the test animal being housed in a closed transparent chamber that substantially prevents contact with ambient air, such as the one disclosed in Patent Publication 1. In that case, the intelligent animals cannot be acclimatized practically, so that small animals that may easily be acclimatized, have to be used, such as mice, rats, and guinea pigs.
For collecting results as closely simulating the assessment for human as possible, it is ideal to conduct all the safety pharmacology studies of a test substance on the same species, in particular on the same individual of animals that are more closely related to human, such as monkeys, dogs, and pigs. However, under the present circumstances, at least the respiratory test has to be conducted on small animals, and is not conducted on a large animal of the same individual as used in the other tests.
In the test and evaluation using small animals, the difference in physiological functions between the small animals and human may sometimes result in production of metabolites that are different from those produced in human. In that case, it is necessary to freshly conduct a test for human metabolites, which delays drug development. Further, various assessment instrument has been developed for the respiratory, central nervous, and cardiovascular tests, but no chamber device has ever been proposed that allows the respiratory test to be conducted on a large animal, such as monkeys, dogs, or pigs, in particular the same individual as used in the other tests, under unanesthetized, unrestrained state, and that allows acclimatization of such animal therein.
Patent Publication 1: U.S. Patent Application Publication No. 2004/254489.